title: Increased CD36 expression in middle-aged mice contributes to obesity-related cardiac hypertrophy in the absence of cardiac dysfunction.
abstract: As aging is a significant risk factor for the development of left ventricular hypertrophy and cardiovascular disease, we hypothesized that hearts from middle-aged mice may be more sensitive to the effects of a high fat (HF) diet than hearts from young mice. To investigate this, young (10-12 week old) and middle-aged (40-44 week old) male mice were fed a low fat (LF) or HF diet (10 or 60 kcal% fat, respectively) for 12 weeks. Following this 12-week period, we show that CD36 protein expression was not changed in hearts from young mice yet was increased 1.5-fold in the middle-aged HF group compared with LF-fed age-matched counterparts. Correlated with increased CD36 expression, middle-aged mice displayed a greater degree of cardiac hypertrophy compared with young mice when fed a HF diet, and this was observed in the absence of cardiac dysfunction. Furthermore, middle-aged CD36 knockout mice were protected against HF diet-induced cardiac hypertrophy, supporting a link between CD36 and cardiac hypertrophy. To further explore potential mechanisms that may explain why middle-aged mice are more susceptible to HF diet-induced cardiac hypertrophy, we investigated mediators of cardiac growth. We show that myocardial ceramide levels were significantly increased in middle-aged mice fed a HF diet compared with LF-fed controls, which was also correlated with inhibition of AMP-activated protein kinase (AMPK). Consistent with AMPK being a negative regulator of cardiac hypertrophy, decreased AMPK activity also resulted in the activation of the mTOR/p70S6K pathway, which is known to enhance protein synthesis associated with cardiac hypertrophy. Together, these data suggest that increased myocardial CD36 expression in hearts from middle-aged mice may contribute to HF diet-induced cardiac hypertrophy and that this may be mediated by elevated ceramide levels signaling through AMPK. Overall, we suggest that inhibition of CD36-mediated fatty acid uptake may prevent obesity-related cardiomyopathies in the middle-aged population.
authors.affiliation: Cardiovascular Research Centre, Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.
authors.forename: Miranda M Y
authors.initials: MM
authors.lastname: Sung
authors.forename: Debby P Y
authors.initials: DP
authors.lastname: Koonen
authors.forename: Carrie-Lynn M
authors.initials: CL
authors.lastname: Soltys
authors.forename: René L
authors.initials: RL
authors.lastname: Jacobs
authors.forename: Maria
authors.initials: M
authors.lastname: Febbraio
authors.forename: Jason R B
authors.initials: JR
authors.lastname: Dyck
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000375:Aging / Q000502:physiology; D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D006332:Cardiomegaly / Q000209:etiology* / Q000378:metabolism*; D009202:Cardiomyopathies / Q000378:metabolism*; D004041:Dietary Fats / Q000009:adverse effects; D015151:Immunoblotting; D008297:Male; D051379:Mice; D009765:Obesity / Q000378:metabolism* / Q000503:physiopathology*
chemical_list: D018955:CD36 Antigens; D004041:Dietary Fats; D055372:AMP-Activated Protein Kinases